When an antigen is presented by a major histocompatibility complex (MHC) on an antigen-presenting cell such as dendritic cell, macrophage, B cell and the like, T cells recognize the antigen via a T cell receptor (TcR/CD3 complex) and are activated. However, an antigen specific signal (first signal) from the T cell receptor alone is not sufficient for the normal activation of T cells, and a second signal called costimulatory signal is essential. Solely with the stimulation by the first signal via TcR, sufficient activation of T cells does not occur, and moreover, T cells fall into the condition called antigen specific T cell unresponsiveness in which T cell cannot respond to the antigen stimulation after the second. As a most important molecule (costimulatory molecule) for transmitting the second signal, CD28 on the T cell is known (Cell, 71, 1065-1068, 1992. Immunology Today, 15, 321-331, 1994). CD28 binds with B7-1 (CD80)/B7-2 (CD86) expressed on an antigen-presenting cell and inserts the second signal into T cells. In fact, stimulation of mouse T cells only with an anti-CD3 antibody does not induce growth of T cells and interleukin (IL)-2 production. However, by the addition of an anti-CD28 antibody in addition to the anti-CD3 antibody, the growth and IL-2 production are drastically enhanced. Therefore, creation of a drug inhibiting the costimulatory signal enables induction of antigen specific immunological tolerance, which possibly leads to the provision of a basic therapeutic drug for various autoimmune diseases.
As a molecule binding with CD80/CD86 like CD28, CTLA-4 is known to be present (Immunity, 1, 405-413, 1994. Biochem. J., 318, 361-377, 1996). While CD28 is constantly expressed in T cell, but CTLA-4 is belatedly expressed after the activation. It has been clarified that the signal from this molecule suppressively acts on the signal from CD28, and regulates the signal from CD28. A fusion protein (CTLA-4-Ig) of an extracellular region of CTLA-4 and immunoglobulin constant region inhibits binding of CD28 and CD80/CD86. The inhibitory action on the CD28 signal has been evaluated using CTLA-4-Ig or an antibody to CD80/CD86 in various mouse disease models. As a result, it has been reported that the inhibition of the CD28 signal shows a striking effect on transplantation (organ transplantation, transplantation of pancreatic islet cell/neuron or bone marrow and the like), autoimmune disease model (collagen induced arthritis, lupus nephritis) and allergic disease model (asthma, dermatitis) (J. Exp. Med., 178, 1801-1806, 1993. J. Exp. Med., 181, 1869-1874, 1995. Nature, 381, 434-438, 1996. J. Immunol., 154, 1481-1490, 1995. Igakuno Ayumi, 193, 787-792, 2000.)
Incidentally, a thienotriazolodiazepine compound is disclosed in WO 94/06801 and WO 94/06802 as a compound having a CCK antagonistic action or gastrin antagonistic action. In addition, WO 93/07129 discloses a compound useful as a therapeutic drug for osteoporosis, WO 93/12117, WO 94/06802, WO 94/22872 and WO 98/11111 disclose a compound having a cell adhesion inhibitory action, WO 97/47622 discloses a compound having a cytokine production suppressive action, and JP-A-1-156982, JP-A-2-243691, JP-A-2-256681, JP-A-2-256682 and JP-A-3-215489 disclose a compound having a platelet-activating factor (PAF) inhibitory activity. However, these publications do not describe or suggest inhibition of costimulatory signal from CD28.    Non-patent reference 1: Cell, 71, 1065-1068, 1992    Non-patent reference 2: Immunology Today, 15, 321-331, 1994    Non-patent reference 3: Immunity, 1,405-413, 1994    Non-patent reference 4: Biochem. J., 318, 361-377, 1996    Non-patent reference 5: J. Exp. Med., 178, 1801-1806, 1993    Non-patent reference 6: J. Exp. Med., 181, 1869-1874, 1995    Non-patent reference 7: Nature, 381, 434-438, 1996    Non-patent reference 8: J. Immunol., 154, 1481-1490, 1995    Non-patent reference 9: Igakuno Ayumi, 193, 787-792, 2000    Patent reference 1: WO 94/06801    Patent reference 2: WO 94/06802    Patent reference 3: WO 93/07129    Patent reference 4: WO 93/12117    Patent reference 5: WO 94/22872    Patent reference 6: WO 98/11111    Patent reference 7: WO 97/47622    Patent reference 8: JP-A-1-156982    Patent reference 9: JP-A-2-243691    Patent reference 10: JP-A-2-256681    Patent reference 11: JP-A-2-256682    Patent reference 12: JP-A-3-215489